Obesity is a heritable disease that affects millions of people, is disproportionately prevalent in the Pima Indians of Southwestern Arizona, and has serious health consequences. The main scientific aims of the Obesity, Diabetes and Energy Metabolism Unit (ODEM) are to study (1) mechanisms of weight gain in Pimas and other human populations and (2) the pathophysiology of type 2 diabetes mellitus in non-obese and obese individuals. - Mechanisms of weight gain in Pimas and other human populations. Using state of the art methods (indirect calorimetry, doubly labeled water and mass spectrometry) to assess energy intake and energy expenditure in free living individuals we demonstrated that low resting metabolic rate and energy intake in excess of daily energy requirements both contribute to body weight gain in adult Pimas. In contrast we found little evidence that that a low level of physical activity precedes the development of obesity. Our data, however, show that that failure to increase physical activity in response to growth may promote obesity and insulin resistance in preadolescence. Using positron emission tomography, a non invasive radiological technique that in recent past allowed us to describe for the first time the map of the human brain responses to hunger, taste and satiation, we were able to demonstrate the existence of abnormal neural activity in the brain of obese vs. lean individuals and obtained initial evidence that some of these abnormalities (increased neural activity in the insular cortex after tasting a little amount of a forthcoming meal and decreased neural activity in the posterior hippocampus after administration of the same meal to satiation) typify individuals who are at increased risk of obesity. We also conducted a series of studies on ghrelin, a novel gastric hormone that may control appetite for food. We were the first to discover that circulating ghrelin is elevated in patients with Prader-Willi syndrome, a genetic disease characterized by insatiable hunger and massive obesity. - Pathophysiology of type 2 diabetes mellitus in non-obese and obese individuals. The adipose tissue is now recognized as an organ that secretes a large number of proteins, which are collectively referred to as adipokines. Our lab has continued to uncover evidence that an adipokine-induced activation of the immune system may mediate the effect of over nutrition on insulin resistance and later development of type 2 diabetes. We are currently conducting a randomized, placebo controlled clinical trial to test if a short treatment with anti-inflammatory drugs improves insulin resistance in non-diabetic obese individuals with high markers of inflammation. We also tested if exaggerated regeneration of cortisol in adipose tissue, which in experimental animals causes the metabolic syndrome, produced similar effects in humans and whether this was more exaggerated in Pimas vs. Caucasians. We found that 11betaHSD1, the enzyme that regenerates active cortisol from inactive cortisone in adipocytes, was elevated in obese, insulin resistant individuals, but did not differ between ethnic groups. However, in a separate study we uncovered evidence that an acute release of cortisol in the circulation more effectively contained sympathoexcitation during stress in Pimas vs. Caucasians, which may be an important mechanism of cardioprotection in this Native American population.